Early Low-Titer Neutralizing Antibodies Impede HIV-1 Replication and Select for Virus Escape

Single genome sequencing of early HIV-1 genomes provides a sensitive, dynamic assessment of virus evolution and insight into the earliest anti-viral immune responses in vivo. By using this approach, together with deep sequencing, site-directed mutagenesis, antibody adsorptions and virus-entry assays, we found evidence in three subjects of neutralizing antibody (Nab) responses as early as 2 weeks post-seroconversion, with Nab titers as low as 1∶20 to 1∶50 (IC50) selecting for virus escape. In each of the subjects, Nabs targeted different regions of the HIV-1 envelope (Env) in a strain-specific, conformationally sensitive manner. In subject CH40, virus escape was first mediated by mutations in the V1 region of the Env, followed by V3. HIV-1 specific monoclonal antibodies from this subject mapped to an immunodominant region at the base of V3 and exhibited neutralizing patterns indistinguishable from polyclonal antibody responses, indicating V1–V3 interactions within the Env trimer. In subject CH77, escape mutations mapped to the V2 region of Env, several of which selected for alterations of glycosylation. And in subject CH58, escape mutations mapped to the Env outer domain. In all three subjects, initial Nab recognition was followed by sequential rounds of virus escape and Nab elicitation, with Nab escape variants exhibiting variable costs to replication fitness. Although delayed in comparison with autologous CD8 T-cell responses, our findings show that Nabs appear earlier in HIV-1 infection than previously recognized, target diverse sites on HIV-1 Env, and impede virus replication at surprisingly low titers. The unexpected in vivo sensitivity of early transmitted/founder virus to Nabs raises the possibility that similarly low concentrations of vaccine-induced Nabs could impair virus acquisition in natural HIV-1 transmission, where the risk of infection is low and the number of viruses responsible for transmission and productive clinical infection is typically one

Peripheral Neuropathic Pain: From Experimental Models to Potential Therapeutic Targets in Dorsal Root Ganglion Neurons

Neuropathic pain exerts a global burden caused by the lesions in the somatosensory nerve system, including the central and peripheral nervous systems. The mechanisms of nerve injury-induced neuropathic pain involve multiple mechanisms, various signaling pathways, and molecules. Currently, poor efficacy is the major limitation of medications for treating neuropathic pain. Thus, understanding the detailed molecular mechanisms should shed light on the development of new therapeutic strategies for neuropathic pain. Several well-established in vivo pain models were used to investigate the detail mechanisms of peripheral neuropathic pain. Molecular mediators of pain are regulated differentially in various forms of neuropathic pain models; these regulators include purinergic receptors, transient receptor potential receptor channels, and voltage-gated sodium and calcium channels. Meanwhile, post-translational modification and transcriptional regulation are also altered in these pain models and have been reported to mediate several pain related molecules. In this review, we focus on molecular mechanisms and mediators of neuropathic pain with their corresponding transcriptional regulation and post-translational modification underlying peripheral sensitization in the dorsal root ganglia. Taken together, these molecular mediators and their modification and regulations provide excellent targets for neuropathic pain treatment

CD40-mediated HIF-1α expression underlying microangiopathy in diabetic nerve pathology

To understand the pathology and molecular signatures of microangiopathy in diabetic neuropathy, we systemically and quantitatively examined the morphometry of microvascular and nerve pathologies of sural nerves. In the endoneurium of diabetic nerves, prominent microangiopathy was observed, as evidenced by reduced capillary luminal area, increased capillary basement membrane thickness and increased proportion of fibrin(+) blood vessels. Furthermore, capillary basement membrane thickness and the proportion of fibrin(+) blood vessels were correlated with small myelinated fiber density in diabetic nerves. In diabetic nerves, there was also significant macrophage and T cell infiltration, and cluster of differentiation 40 (CD40) expression was increased. The molecular alterations observed were upregulation of hypoxia-inducible factor-1α (HIF-1α), mitogen-activated protein kinase-activated protein kinase 2 (MK2; MAPKAPK2) and phosphatase and tensin homolog (PTEN). In addition, HIF-1α was correlated with small myelinated fiber density and capillary luminal area, while both MK2 and PTEN were correlated with capillary basement membrane thickness. The molecular cascades were further demonstrated and replicated in a cell model of microangiopathy on human umbilical vein endothelial cells (HUVECs) exposed to high-glucose medium by silencing of CD40, PTEN and HIF-1α in HUVECs using shRNA. These data clarified the hierarchy of the molecular cascades, i.e. upregulation of CD40 leading to HIF-1α expression in endothelium and nerve fibers. In conclusion, this study revealed the association of microangiopathy, thrombosis and inflammatory infiltrates with nerve degeneration in diabetic nerves, demonstrating that CD40 is a key molecule for the upregulation of HIF-1α and PTEN underlying the severity of microangiopathy

Unique clinical characteristics and SCN5A mutations in patients with Brugada syndrome in Taiwan

Brugada syndrome (BrS) is a hereditable sudden cardiac death (SCD). Mutations in the SCN5A gene (the most common BrS-causing gene) are responsible for 20–25% of this disease in Caucasian populations. However, the prevalence of SCN5A mutations in patients with BrS in the Chinese Han population in Taiwan remains unknown. Therefore, in this study, we investigated the prevalence of the SCN5A mutation in the largest BrS cohort in Taiwan. Methods: We consecutively enrolled 47 unrelated patients with BrS from medical centers and hospitals in Taiwan between 2000 and 2010. Mutations within all the 27 translated exons, and exon–intron boundaries of the SCN5A-encoded cardiac sodium channel were screened in all patients with BrS using direct sequencing. A total of 500 unrelated healthy volunteers with a normal electrocardiogram were genotyped as a control group. Results: SCN5A genetic variants were identified in 14 of the 47 patients with BrS and four of the 14 patients with BrS had missense mutations (1651 G>A, 1776 C>G, 3578 G>A). The prevalence rate of SCN5A mutations was approximately 8% (4/47), which was significantly lower than that reported in Caucasian populations (20–25%; p = 0.0007). The average age of these 14 BrS patients with SCN5A variants at diagnosis (12 men and 2 women) was 40 ± 13 years. Four patients experienced SCD, and six presented with seizure or syncope. Only three patients (3/14, 21.4%) had a family history of SCD. Conclusion: The prevalence of SCN5A mutations in the Chinese Han population in Taiwan may be lower than that reported in the Caucasian populations. In addition, most patients with BrS did not have a family history of SCD

Gastroesophageal reflux disease and risk for bipolar disorder: a nationwide population-based study.

BACKGROUND: Studies have shown that chronic inflammation may play a vital role in the pathophysiology of both gastroesophageal reflux disease (GERD) and bipolar disorder. Among patients with GERD, the risk of bipolar disorder has not been well characterized. OBJECTIVE: We explored the relationship between GERD and the subsequent development of bipolar disorder, and examined the risk factors for bipolar disorder in patients with GERD. METHODS: We identified patients who were diagnosed with GERD in the Taiwan National Health Insurance Research Database. A comparison cohort without GERD was matched according to age, sex, and comorbidities. The occurrence of bipolar disorder was evaluated in both cohorts based on diagnosis and the prescription of medications. RESULTS: The GERD cohort consisted of 21,674 patients, and the comparison cohort consisted of 21,674 matched control patients without GERD. The incidence of bipolar disorder (incidence rate ratio [IRR] 2.29, 95% confidence interval [CI] 1.58-3.36, P<.001) was higher among GERD patients than among comparison cohort. Multivariate, matched regression models showed that the female sex (hazard ratio [HR] 1.78, 95% CI 1.76-2.74, P = .008), being younger than 60 years old (HR 2.35, 95% CI 1.33-4.16, P = .003), and alcohol use disorder (HR 4.89, 95% CI 3.06-7.84, P = .004) were independent risk factors for the development of bipolar disorder among GERD patients. CONCLUSIONS: GERD may increase the risk of developing bipolar disorder. Based on our data, we suggest that attention should be focused on female patients younger than 60 years, and patients with alcohol use disorder, following a GERD diagnosis

Cardiac Mechanics and Ventricular Twist by Three-Dimensional Strain Analysis in Relation to B-Type Natriuretic Peptide as a Clinical Prognosticator for Heart Failure Patients

<div><p>Background</p><p>Three dimensional (3D) echocardiography-derived measurements of myocardial deformation and twist have recently advanced as novel clinical tools. However, with the exception of left ventricular ejection fraction and mass quantifications in hypertension and heart failure populations, the prognostic value of such imaging techniques remains largely unexplored.</p><p>Methods</p><p>We studied 200 subjects (mean age: 60.2±16 years, 54% female, female n = 107) with known hypertension (n = 51), diastolic heart failure (n = 61), or systolic heart failure (n = 30), recruited from heart failure outpatient clinics. Fifty-eight healthy volunteers were used as a control group. All participants underwent 3D-based myocardial deformation and twist analysis (Artida, Toshiba Medical Systems, Tokyo, Japan). We further investigated associations between these measures and brain natriuretic peptide levels and clinical outcomes.</p><p>Results</p><p>The global 3D strain measurements of the healthy, hypertension, diastolic heart failure, and systolic heart failure groups were 28.03%, 24.43%, 19.70%, and 11.95%, respectively (all <i>p</i><0.001). Global twist measurements were estimated to be 9.49°, 9.77°, 8.32°, and 4.56°, respectively. We observed significant differences regarding 3D-derived longitudinal, radial, and global 3D strains between the different disease categories (<i>p</i><0.05), even when age, gender, BMI and heart rate were matched. In addition, 3D-derived longitudinal, circumferential, and 3D strains were all highly correlated with brain natriuretic peptide levels (<i>p</i><0.001). At a mean 567.7 days follow-up (25^th–75^th IQR: 197–909 days), poorer 3D-derived longitudinal, radial, and global 3D strain measurements remained independently associated with a higher risk of cardiovascular related death or hospitalization due to heart failure, after adjusting for age, gender, and left ventricular ejection fraction (all <i>p</i><0.05).</p><p>Conclusions</p><p>3D-based strain analysis may be a feasible and useful diagnostic tool for discriminating the extent of myocardial dysfunction. Furthermore, it is able to provide a prognostic value beyond traditional echocardiographic parameters in terms of ejection fraction.</p></div

The cut-off values of each strain parameter or twist for clinical outcome prediction.

<p>Abbreviations: 3D: 3-dimensional, S: strain.</p><p>The cut-off values of each strain parameter or twist for clinical outcome prediction.</p